Although transplantation of organs is becoming commonplace, rejection of the donated organ by the patient remains a serious problem. Almost all transplant recipients require an immunosuppressive regimen to prevent such rejection. However, immunosuppressive drugs also suppress the body's defenses against infection. Thus, transplantation requires a continuous effort to induce acceptance of the graft without paralyzing the body's immune system and without the additional stress of undesirable side effects produced by the immunosuppressive drug itself.
When an allograft, such as kidney, liver or heart, is transferred from one mammal across a strong histocompatibility barrier to another, the allograft is initially vascularized and the recipient's immune cells begin to proliferate. After about 10 days the allograft becomes the site of intense inflammation and the allograft is infiltrated by lymphocytes which leads to the rejection of the tissue. This type of rejection reaction is due primarily to the action of T-lymphocytes or the cell-mediated immune response of the recipient host to the allograft.
In mammals, precursors of active T-lymphocytes are activated by their contact with an antigen. After contact, the lymphocytes enlarge, enter into the mitotic cycle, proliferate and acquire specific cytolytic activity. Suppression of rejection is usually directed at preventing the T-lymphocytes from proliferating.
A typical regimen for immunosuppression, starting before or at the time that the transplantation is performed comprises one or more of the following agents or therapies: (1) corticosteroids, such as prednisone or prednisolone; (2) inhibitors of nucleic acid synthesis, such as azathioprine, cyclophosphamide and mycophenolic acid; (3) T-cell inhibitors, such as cyclosporin and FK-506; (4) therapies such as x-ray irradiation; and (5) polyclonal and monoclonal anti-lymphocyte and antithymocyte antibodies.
All of these therapy methods have undesirable side effects. Many transplant recipients face serious infection from opportunistic organisms including bacteria, fungi, protozoa and viruses. Some types of cancer are as much as 100 times more frequent in transplant recipients. The corticosteroids may additionally cause diabetes mellitus, osteoporosis and cataracts. The cytotoxic agents may cause anemia, hypertension, thrombocytopenia and damage to the liver and bladder. Cyclosporin may cause decreased renal function, hypertension and undesirable effects on the central nervous system.
Acute rejection may respond or is prevented by currently available immunosuppressive agents. Clinical manifestations of acute renal transplant rejection may include fever, graft swelling or tenderness, oliguria, and increases in blood urea nitrogen (BUN) and serum creatinine levels. Rejection of a transplanted liver or heart leads to the loss of the important metabolic and cardiovascular functions of these organs.
It is desirable that a composition, and method of use of such a composition is developed, which is effective when administered after the rejection reaction (described above) has been initiated. Such administration avoids unnecessary treatment if a rejection reaction to a transplanted organ is delayed or does not develop. The ability to postpone treatment minimizes the side effects of the immunosuppressive agent by reducing the overall period of time required for treatment, or enables new treatments to be initiated when a previouly used treatment has not been effective.